title: Clicking 3'-azidothymidine into novel potent inhibitors of human immunodeficiency virus.
abstract: 3'-Azidothymidine (AZT) was the first approved antiviral for the treatment of human immunodeficiency virus (HIV). Reported efforts in clicking the 3'-azido group of AZT have not yielded 1,2,3-triazoles active against HIV or any other viruses. We report herein the first AZT-derived 1,2,3-triazoles with submicromolar potencies against HIV-1. The observed antiviral activities from the cytopathic effect (CPE) based assay were confirmed through a single replication cycle assay. Structure-activity-relationship (SAR) studies revealed two structural features key to antiviral activity: a bulky aromatic ring and the 1,5-substitution pattern on the triazole. Biochemical analysis of the corresponding triphosphates showed lower ATP-mediated nucleotide excision efficiency compared to AZT, which along with molecular modeling suggests a mechanism of preferred translocation of triazoles into the P-site of HIV reverse transcriptase (RT). This mechanism is corroborated with the observed reduction of fold resistance of the triazole analogue to an AZT-resistant HIV variant (9-fold compared to 56-fold with AZT).
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Venkata Ramana
authors.initials: VR
authors.lastname: Sirivolu
authors.forename: Sanjeev Kumar V
authors.initials: SK
authors.lastname: Vernekar
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ilina
authors.forename: Nataliya S
authors.initials: NS
authors.lastname: Myshakina
authors.forename: Michael A
authors.initials: MA
authors.lastname: Parniak
authors.forename: Zhengqiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D015215:Zidovudine